SUMMARY Retinal neuronal death causes vision loss and blindness. Yet there is no therapy available to effectively protect retinal neurons. This application proposes continuation of a project designed to elucidate common mechanisms that control retinal neuronal injury in retinopathy. During the previous funding period, we demonstrated that endoplasmic reticulum (ER) stress-induced CXL10/CXCR3 axis has a key role in retinal inflammation, oxidative stress and neuronal injury. Our data suggest a model in which injured or stressed retinal neurons (e.g. retinal ganglion cells (RGCs)) release CXCL10 that directly induces RGC death by activating the cAMP/Epac1 pathway and indirectly causes RGC damage by recruiting and activating leukocytes from blood. Epacs (Epac1 and Epac2) are novel mediators of cAMP. We now propose to determine the central role of Epac1 in linking multiple insults in ischemic retinopathy to neuronal injury and further investigate the interactions between neurons and vessels. Our hypothesis is that Epac1 activation plays a causal role in retinal neuronal and vascular injury in ischemic retinopathy and pharmacologic inhibition of Epac provides a novel therapeutic intervention for ischemic retinopathy. This application will, for the first time, use Epac1 global KO mice, Epac1 conditional KO mice, AAV2-mediated gene delivery, novel Epac inhibitor, non- invasive advanced imaging and functional testing to investigate the cAMP/Epac1 pathway in retinal neuronal and vascular injury in mouse models of acute and chronic ischemic retinopathy. It will also investigate potential mechanisms of Epac1-induced retinal neuronal damage and subsequent vascular alterations. The research is expected to significantly advance the mechanistic understanding of ischemic retinopathy and should facilitate the development of novel strategies to protect retinal neurons and vessels in ischemic retinopathy. This proposal directly addresses vision research priorities identified in the NEI Publication, ?Vision Research: Needs, Gaps, & Opportunities?: 1) Apply molecular biology techniques to RGC neuroscience to dissect factors important for survival, axon regeneration, and physiology. 2) Explore neuroprotection as an approach for prolonging RGC function and survival.